May 2, 2013
The ITN’s Spring 2013 Network Steering Committee (NSC) meeting was held in Boston, with a new meeting format that included structured group discussions focused on new therapeutic approaches proposed for consideration by the ITN, as well as presentations of data from ongoing and recently completed ITN studies.
The meeting started with presentations and discussion centered on specific trials where recently obtained data warranted broader NSC input. Nadia Tchao, MD (ITN) led off the discussion presenting the 18-month data from the RAVE study (Rituximab for the Treatment of ANCA-associated Vasculitis and Microscopic Polyangiitis) using TrialShare as a vehicle for viewing figures and data. The 18-month data continue to look very impressive, with no differences in remission rate or disease flares between the rituximab (short, single course) and control group (cyclophosphamide-azathioprine standard of care). The presentation addressed ways to use RAVE data to investigate biomarkers and mechanisms that better predict disease flares, and to think about ways to modify future study designs that may combine rituximab induction with other modulators to improve upon the success rate.
Larry Turka, MD (ITN; Massachusetts General Hospital) presented data on T cell receptor (TCR) repertoire reconstitution following autologous bone marrow transplant in the HALT-MS study (High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis), using a novel deep sequencing method to provide unprecedented detail. At 2 months post-transplant patients showed significantly less TCR diversity in both CD4 and CD8, (although the kinetics of reconstitution is different between these subsets) while at 1 year post-transplant the diversity begins to look like baseline but is not identical. In a subset of subjects the CD4 repertoire, but not the CD8 repertoire, was entirely ablated, and a completely new repertoire of CD4 TCR emerged after transplantation; the relationship to therapy awaits completion of the study.
Mario Ehlers, MD, PhD (ITN) presented new results that have emerged since the primary endpoint analysis of the START study (Study of Thymoglobulin to Arrest Newly Diagnosed Type 1 Diabetes). Although the study did not reach its primary 12-month endpoint and there appeared to be an unfavorable Teff to Treg ratio, a subsequent analysis indicated a potential difference in treatment effect between younger and older subjects, where older ATG-treated subjects show preservation of c-peptide at 12 months compared to the younger treated subjects who exhibit a decline. This data was discussed along with preliminary data from the University of Florida ATG-GCSF study presented by Mark Atkinson, PhD, where the combination of ATG with GCSF seems to preserve and improve c-peptide over 12 months in subjects with established diabetes, relative to controls.
Betty Diamond, MD (The Feinstein Institute for Medical Research) presented the primary endpoint data from the ACCESS study (Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis). The study did not meet the primary endpoint (no difference in complete response between the treatment and control arm), but we will await the 12-month data (available in June) to determine whether there are differences between the groups over longer periods.
Mark Rigby, MD (Indiana University) presented very recently-completed primary endpoint data from the T1DAL study (Inducing Remission in New Onset T1DM with Alefacept (Amevive®)). The study was unable to enroll the full intended cohort due to Alefacept (LFA3-Ig) availability issues, but the treatment arm experienced no decline in c-peptide at 12 months compared to baseline, an unusual finding for type 1 diabetes studies (although did not quite reach statistical significance over placebo possibly due to the reduced sample size and imbalance of age and gender controls). Mechanistic analyses are underway, and the team is awaiting the 18 and 24 month outcomes.
The presentations from all the above sessions are posted for internal access on the Document Portal.
In order to better evaluate whether the ITN should be involved in some novel therapeutic approaches that have been proposed to the NSC, we invited experts from three different fields to discuss the current state of research in their areas of expertise. For each area the goal was to determine what would need to be demonstrated before initiating tolerance studies, and what would likely be feasibility/design/disease considerations for the ITN.
Alan Krensky, MD (Northwestern University) chaired the Microbiome Manipulation Strategic Assessment, which included Richard Blumberg, MD (Harvard University), Cathy Nagler, PhD (University of Chicago), Mark Atkinson, PhD (University of Florida), Jim Rosenbaum, MD (Oregon Health and Science University) and Liam O’Mahony, PhD (Swiss Institute for Allergy and Asthma Research). The speakers presented exploratory work in animals and humans on the role of the gut microbiome in influencing autoimmunity and allergy, but much is still not known about how to clinically intervene in a manner that can change the course of disease. Studies need to combine therapeutics with understanding of the microbial pathways that can be manipulated and targeted for certain disease indications in a way that can create a stable change in immune functioning.
Kathryn Wood, MD (University of Oxford) chaired a Regulatory T Cell Strategic Assessment, including Edward Geissler, PhD (University of Regensburg), Jeff Bluestone, PhD (University of California, San Francisco), David Klatzmann, MD (UPMC Sorbonne), Megan Sykes, MD (Columbia University) and Andrew Luster, MD (Harvard University). The presenters shared data from early human studies using Tregs in type 1 diabetes and uveitis, both demonstrating good safety. Investigators in Europe and the United States are participating in the ONE Study, which is intended to expedite the evaluation of multiple forms of cellular therapeutics in kidney transplant using the same protocol to enable comparisons. The ITN may be well positioned to help developing combination strategies that incorporate regulatory cell therapy, which will necessitate completion of these early human trials. The autoimmunity and transplant assessment groups will continue to discuss the optimal platforms and therapeutic approaches for Tregs.
Jim Markmann, MD, PhD (Massachusetts General Hospital), Steve Miller, PhD (Northwestern University) and Ulrich von Andrian, MD (Harvard University; Selecta Biosciences) spoke to the group about the use of biocompatible nanoparticles and fixed cells for antigen delivery in potential tolerogenic therapies. The speakers demonstrated that there has been tremendous progress since the ITN first became interested in this approach and described rapid development of nanoparticle therapy that is replacing the early fixed-cell therapy previously considered. Several opportunities for ITN involvement are possible upon the completion of phase I studies (for which the ITN could partner on mechanistic studies). Proof-of-concept studies using enzyme replacement therapy are one example that could be considered as a tolerogenic demonstration project.
The ITN will follow up with each of these therapeutic approaches within our disease-area specific assessment groups and we will continue to engage the invited speakers to keep tabs on their progress.
Jerry Nepom, MD, PhD (ITN; Benaroya Research Institute) and Dan Rotrosen, MD (NIAID) gave a tribute to George Eisenbarth, MD, a founding member of the ITN’s NSC and a pioneer in the type 1 diabetes community, who passed away in November of 2012. Dr. Eisenbarth made great contributions to the field of type 1 diabetes, where his work contributed to the understanding of the autoimmune nature of the disease and the application of this knowledge to new treatment approaches. The community is indebted to his efforts.
The ITN also had the unique pleasure of meeting Jennifer Searl, the first patient to be enrolled in the Mixed Chimerism study led by David Sachs, MD (Massachusetts General Hospital). A resident of Boston, Jennifer was kind enough to speak to the NSC about her experiences being in an ITN trial. Following her combined bone marrow and kidney transplant over 10 years ago she was successfully weaned from immunosuppression and has been tolerant ever since. She spoke about how much her life has improved without the burden of immunosuppression, and thanked the group for the important work they do to advance tolerance.
In his State of the Network, Jerry Nepom highlighted the strength of the ITN’s current portfolio and pipeline. Although the upcoming contract transition places a moratorium on new studies, it provides an opportunity to reflect on the ITN’s priorities, determine opportunities for our current resources (like available samples in the repository) and identify ways to be more efficient. The ITN is looking forward to the upcoming months with more strategic discussions and engagement with the NSC on new projects.
More Information